Faculty Bibliography

Background: Patients (pts) who are triple-class-exposed to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor clinical outcomes on subsequent lines of treatment and limited treatment options.
Aim(s): To identify published evidence for therapies that have been investigated or currently used in triple-class exposed pts with relapsed and refractory multiple myeloma (RRMM).
Method(s): Searches were performed 6 January 2020 in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials databases. Eligible studies had to have been completed <=5 years before the search date. Relevant conference proceedings for 2018 and 2019 were also included in the search. Study quality assessment included use of the Downs and Black checklist. Studies that did not explicitly require previous anti- CD38 mAb exposure but reported the proportion of pts who received this drug class were included.
Result(s): There were 24 studies identified; 11 real-world studies and 13 clinical trials. The Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure (MAMMOTH), a retrospective chart review of MM pts from 14 US academic centers, was the largest real-world study (Leukemia. 2019;33:2266-75). All pts (N = 275) were refractory to daratumumab or isatuximab and 249 received subsequent therapy after anti-CD38 therapy. The overall response rate (ORR) to the first regimen after anti-CD38 therapy was 31% overall and was 29% in the combined triple-refractory and quad-refractory subgroup (N = 148). Median progression-free survival (PFS) and overall survival (OS) after subsequent therapy was 3.4 and 9.3 months, respectively, among those who received >=1 subsequent regimen in the overall population. Other real-world studies were limited to abstracts or had a high risk of bias; ORR and median OS rarely exceeded 30% and 10 months, respectively. Three phase II clinical trials evaluated interventions that are approved or under consideration by the US FDA. STORM part 1 and part 2, assessed selinexor plus dexamethasone, a combination granted accelerated approval in the US for a highly refractory post-daratumumab population (RRMM pts with >=4 prior regimens and refractory to >=2 PIs, >=2 immunomodulatory drugs, and an anti-CD38 mAb); STORM part 2, which also included pts triple-class exposed to daratumumab, an immunomodulatory drug, and a PI (N = 122), reported an ORR of 26% and a complete response rate of 2%. The median duration of response was 4.4 months, median PFS was 3.7 months, and median OS was 8.6 months. The other phase II study, DREAMM-2, investigated belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) in RRMM. This study evaluated 196 pts refractory to immunomodulatory drugs and PIs, and refractory/ intolerant to an anti-CD38 mAb. After a median follow-up of 6.3 months (2.5 mg/kg cohort, n = 97) and 6.9 months (3.4 mg/kg cohort, n = 99), ORR was 31% and 34%, respectively. Median PFS was 2.9 months (2.5 mg/kg) and 4.9 months (3.4 mg/kg). Median OS was not reported. Summary/Conclusion: Results from this systematic literature review (SLR) indicate that only limited efficacy data are available for therapies investigated in RRMM pts who have had prior exposure to an immunomodulatory agent, a PI, and an anti-CD38 mAb. Outcomes are generally poor, supporting an urgent need for better treatment options for triple-class-exposed pts with RRMM. The studies identified in this SLR provide a benchmark against which therapies in development, such as emerging BCMA-directed therapies, can be compared

PURPOSE/OBJECTIVE:Copy number changes and translocations have been studied extensively in many datasets with long term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. METHODS:we performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the Total Therapy Trials (TT). RESULTS:As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF making up 44% of patients. Double-Hit, BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF mutated patients showed co-occurring alterations in KRAS, NRAS or activating BRAF mutations suggesting they play a role in the oncogenesis of multiple myeloma (MM) by facilitating MAPK activation and may lead to chemo resistance. CONCLUSION/CONCLUSIONS:Overall, these data highlight the importance of mutational screening to better understand newly diagnosed MM (NDMM) and may lead to patient specific mutation-driven treatment approaches.

Preclinical data suggests that bortezomib can inhibit genotoxic stress response pathways and thereby restore sensitivity to DNAdamaging chemotherapeutic agents. This was the rationale for this study combining bortezomib with two chemotherapy agents. The trial recruited patients from 2006 to 2013 but has never been analysed or reported and provides insights into the role of standard chemotherapy agents in relapsed myeloma, for which there is little published evidence. VIM was a single centre phase 1/2 study of bortezomib, idarubicin and melphalan in relapsed or refractory myeloma. Phase 1 was a 3+3 design with escalating doses of idarubicin and melphalan in combination with 1.3 mg/m2 bortezomib administered on D1,4,8,11 on a 4 weeks cycle. Phase 2 was dose expansion at the maximum tolerated dose (MTD) in a further 20 patients to explore efficacy. Treatment was for 3 cycles. Following VIM, patients were allowed to directly proceed to other treatments including autologous transplant (ASCT). The primary objective was safety and tolerability. Secondary endpoints were response, Progression Free and Overall Survival (PFS, OS). Key inclusion criteria were relapsed or refractory myeloma following >=1 previous therapies, platelet count >=70 x109/L, white cell count >=3.0 x109/L and creatinine clearance of >=40 mls/min. Dose limiting toxicity was defined as any grade 4 non-haematological toxicity, any grade 3 nonhaematological toxicity not resolving to grade 2 within 2 weeks of end of cycle and any grade 4 haematological toxicity except neutropenia not resolving to grade 3 within 2 weeks of end of cycle. The study recruited 3, 3, 7 patients on dose levels 1, 2 and 3 respectively during the dose escalation phase. The MTD dose was defined as level 2 which was: Idarubicin 5 mg/m2 PO D4, 5; melphalan 15 mg/m2 IV D4; bortezomib 1.3 mg/m2 D1, 4, 8, 11 on a 4 weeks cycle. An additional 20 patients were recruited to the dose expansion phase. Median patient age was 62. Median prior lines of therapy was 4 (range 2-8). Adverse Events at the MTD level are listed in table 1. The main toxicity was haematological, with 74% of patients having grade >=3 neutropenia, 78% grade >=3 thrombocytopenia. 26% of patients experienced grade >=3 infective complications. There were 3 deaths on treatment; all had progressive or refractory disease at time of death, two with concurrent respiratory infection but neither were neutropenic or directly treatment related. In the intention to treat (ITT) cohort, the overall response rate (ORR) was 79%, with 46% achieving >=very good partial response (VGPR) of which 14% were near complete response (nCR, defined as no paraprotein by serum protein electrophoresis and <5% plasma cells on trephine but without immunofixation to confirm CR). In the MTD cohort the ORR was 85%, with 50% >=VGPR and 20% nCR. PFS reflects the heterogeneity of treatment after VIM, including ASCT. Median OS was 19.0 months in the ITT cohort and 26.1 months in the MTD cohort. Treatment options at relapse have multiplied since this trial was designed. However, VIM is a generic, relatively inexpensive, steroid free regimen with defined toxities and significant efficacy. The main side effects, as expected, were haematological. Responses were higher than expected for median 5th line therapy suggesting possible synergy in this combination and reminding us that standard chemotherapies can have a role in relapsed myeloma if other options are unavailable and blood counts are reasonable

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.

As multiple myeloma (MM) treatments evolve, frequent updates are required to monitor the long-term effect of changes in approach. Traditionally, MM is considered an incurable disease, with most patients eventually relapsing. However, improvements in treatments has raised the possibility that MM might be functionally curable. To examine improvements in long-term survival, we followed 4329 patients with newly diagnosed MM treated with autologous stem cell transplantation (ASCT) at the University of Arkansas for Medical Sciences from 1989 through 2018. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox proportional hazards models, relative survival analysis, and cure modeling among different time periods, risk groups, and demographic traits. Steady improvements in OS were found, with patients treated in 2014 or later having superior OS (hazard ratio, 0.35; 95% confidence interval [CI], 0.27-0.45) and reduced excess risk for MM death (relative excess risk, 0.30; 95% CI, 0.22-0.41) compared with patients treated in 1997 or earlier. Patients treated during intervening time periods often had intermediate survival, but trends in OS, PFS, and landmarked analyses were inconsistent. Cure models support the potential for cure, ranging from 6.3% to 31.3%, depending on the year of treatment, with 10.0% to 18.6% of patients achieving their normal life expectancy across multiple periods. There was some evidence of reductions in early mortality within 3 years of diagnosis, longer complete response (CR) duration, and reductions in relapse after achieving CR. However, results differed depending on age, risk group, and cytogenetic characteristics.

BACKGROUND:Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS:subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS/RESULTS:Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION/CONCLUSIONS:Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING/BACKGROUND:Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.

Background: Structural variants are key recurrent molecular features of myeloma (MM) with two types of complex rearrangement, chromoplexy and chromothripsis, having been described recently. The contribution of these to MM prognosis, rapid changes in clinical behavior and punctuated evolution is currently unknown as is the mechanism by which they deregulate gene function. XXMethod(s): We analyzed two sets of newly diagnosed MM data: 85 cases with phased whole genome sequencing; and 812 cases from CoMMpass where long-insert whole-genome sequencing was available. Patient derived xenografts from five MM cases were used to generate epigenetic maps for the histone marks, BRD4, MED1, H3K27Ac, H3K4me1, H3K4me3, H3K9me3, H3K36me3 and H3K27me3. XXResult(s): In the 10X data the median number of structural events per case was 25 (range 1 - 182); with a median of 14 intra-chromosomal events (range 1 - 179; P<0.001) and 7 inter-chromosomal events (range 0 - 29). Structural events were seen most frequently on chromosomes 14 (64%), 8 (53%), 1 (44%) and 6 (42%). Complex chromosomal rearrangements involving 3 or more chromosomal sites were seen in 46%, 4 or more sites in 20%, 5 or more in 10% and 6 or more in 5% of samples. There were significantly more structural events in the t(4;14) subgroup compared to the t(11;14) subgroup. Significantly more events were also seen in the bi-allelically inactivated TP53 cases. Using an elbow test defined cutoff, we identified cases with high structural variant load in 10% of cases. Chromoplexy called by "Chainfinder" was seen in 18% of cases. Chromothripsis called by "Shatterseek" was seen in 9% of cases. Cases with a high structural load alone were not associated with an adverse outcome whereas cases with chromoplexy or chromothripsis were associated with adverse PFS and OS, p=0.001. A new high-risk subgroup comprising approximately 5% of cases was identified with chromoplexy, chromothripsis and a high structural load. Gene set enrichment analysis of cases with chromoplexy and chromothripsis showed an excess of MYC, E2F and G2M targets, and a reduction in RAS signaling. Interferon a and g responses, an excess of TP53 and reduction in TRAF3 mutations was associated predominantly with chromothripsis. How chromoplexy and chromothripsis are tolerated by the cell is unknown and the association with the cGAS/STING response is further being explored. To determine how chromoplexy may deregulate multiple genes we identified the full spectrum of structural variants to the immunoglobulin (Ig) and non-Ig loci. A range of genes are deregulated by Ig loci including MAP3K14 at a frequency of 2% confirming the importance of non-canonical NFkB signaling. A novel intra-chromosomal rearrangement to ZFP36L1 was upregulated in 10% of cases but was not prognostic. Gene upregulation by non-Ig super enhancers is frequent and targets include PAX5, GLI3, CD40, NFKB1, MAP3K14, LRRC37A, LIPG, PHLDA3, ZNF267, CENPF, SLC44A2, MIER1, SOX30, TMEM258, PPIL1, and BUB3. The topologically associating domain (TADs) containing super enhancers bringing about gene deregulation include TXNDC5, FOXO3, FCHSD2, SP2, FAM46C, CACNA1C, TLCD2 and PIK3C2G. These super enhancers frequently contain important MM genes, the coding sequence of which are disrupted by the rearrangement and could contribute to the clinical phenotype. Accurately reconstructing the structure of the complex rearrangements will allow us to identify the mechanism of gene deregulation and to distinguish between either gene stacking, receptor stacking or both. XXConclusion(s): Upregulation of gene expression by super enhancer rearrangement is a major mechanism of gene deregulation in MM and complex structural events contribute significantly to adverse prognosis by a range of mechanisms as well as simple gene overexpression. Disclosures: Boyle: Amgen, Abbvie, Janssen, Takeda, Celgene Corporation: Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Walker: Celgene: Research Funding. Thakurta: Celgene: Employment, Equity Ownership. Flynt: Celgene Corporation: Employment, Equity Ownership. Davies: Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan: Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding.XXCopyright

MRD is a powerful predictor of survival outcomes in multiple myeloma but treatment regimens show increasing duration and complexity for both TE and TNE populations. For this reason, sequential assessments are preferable to single timepoints. This has been evaluated in the Myeloma XI trial, which was a phase 3 trial with three potential randomisations to determine induction therapy, consolidation therapy and maintenance in both TE and TNE patients. Bone marrow aspirates were obtained after induction, post consolidation (if given), post ASCT for TE patients and 6 months post maintenance randomisation. MRD was assessed using flow cytometry (minimum sensitivity 0.004%). This analysis represents a subset of 1630 samples that represent all patient groups and therapeutic timepoints. Overall MRD-negativity post-induction was 164/722 (22.7%). 70.1% of patients randomised to CCRD were MRD-negative compared to 19.6% after CTD or RCD in TE patients and 12.7% after CTDa and 19.2% after RCDa (p <0.001) in TNE patients. Levels of residual disease in MRD-positive patients were lower following CCRD induction; median 0.08% of leucocytes (range 0.001-9.5%), compared to medians of 0.31%, 0.23%, 0.38% and 0.42% following CTD, RCD, CTDa and RCDa respectively. MRD-negativity was demonstrated in 16/54 (29.7%) of patients who received bortezimib-based consolidation following a suboptimal response to induction. Post ASCT, 257/413 (62%) of samples were MRD-negative, with a significant increase in MRD-negativity rate relative to post induction seen with CTD (59.2% vs 19.6% post induction) and RCD (53.6% vs to 19.6% post induction). The level of conversion from MRD-positive post induction to MRD-negative post-ASCT was lower in the CCRD cohort (83.3% MRD-negative post ASCT compared to 70.1% following induction). Amongst the patients who underwent maintenance randomisation, MRD-negativity was demonstrated in 238/413 (57.6%). Conversion to MRD-negativity was seen in 32% of MRD-positive patients on lenalidomide maintenance, whilst those patients who became MRD-positive during maintenance had poor outcome. For those patients that remained MRD-positive, lower levels of residual disease were noted in those receiving maintenance (median 0.15% on maintenance vs 0.39%, p=0.04). Sequential MRD monitoring allows for the assessment of individual components of complex myeloma therapeutic strategies. It enables comparison of induction regimens, possibly identifying patients that may not require ASCT. Consolidation or maintenance strategies can also be assessed. This data suggests a potential future role for flow cytometric MRD assessment in individual patient management. A full dataset of >4000 samples and mature outcome data will be presented at the meeting. Keywords: Flow Cytometry Minimal residual disease Tracks: Myeloma Response Assessment including MRD
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